The long-term objective of this research program is to study the failure of neural mechanisms that regulate vascular resistance during orthostatic intolerance in humans. This proposal will study the muscle sympathetic nerve activity and peripheral vascular responses to orthostatic stress in humans who suffer from either recurrent episodes of vasovagal syncope or postural orthostatic tachycardia syndrome (POTS). The current dogma is that, during vasovagal syncope, "over stimulation" of cardiopulmonary mechanoreceptors causes marked inhibition of the vasomotor center and subsequent bradycardia and an inappropriate fall in sympathetic vasoconstrictor activity to the periphery. In POTS, patients manifest marked tachycardia in response to standing that may be related to inadequate peripheral vasoconstriction in the upright posture. The general hypothesis under study in both these patient groups is that orthostatic stress evokes either inadequate sympathetic vasoconstrictor outflow or inadequate peripheral vasoconstriction in response to a normal rise in sympathetic outflow during orthostatic stress. Additionally, in vasovagal syncope, a major unresolved issue is whether the marked vasodilation that occurs during syncope is the result of sympathetic withdrawal or active vasodilation. These concepts will be studied by addressing the following specific aims: Specific Aim 1 - What are the temporal an quantitative relationships between central venous pressure, arterial blood pressure, calf compliance, muscle sympathetic nerve activity, heart rate, and forearm vascular resistance during lower body negative pressure in patients with recurrent vasovagal syncope? Specific Aim 2 - What are the temporal and quantitative relationships between central venous pressure, arterial blood pressure, calf compliance, muscle sympathetic nerve activity, heart rate, and forearm vascular resistance during lower body negative pressure in patients with POTS? Specific Aim 3 - Does neurally mediated nitric oxide (NO) release contribute to the marked peripheral vasodilation observed during vasovagal syncope in humans? These specific aims will be studied in normal humans and patients with either recurrent vasovagal syncope or POTS during venous pooling caused by lower body negative pressure (LBNP). During the venous pooling, arterial blood pressure, central venous pressure, forearm blood flow, calf compliance, and muscle sympathetic nerve activity will be measured. In some studies, local anesthetic block of the stellate ganglion will be used to eliminate autonomic outflow tot he upper extremity. In other studies, nitric oxide synthase inhibitors will be infused into the brachial artery to evaluate the contribution of nitric oxide to peripheral vasodilation during mental stress and vasovagal syncope. Execution of these studies will provide mechanistic information concerning the reflex regulation of vascular resistance during orthostatic intolerance in humans.